Metformin: an old but still the best treatment for type 2 diabetes
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6
http://www.dmsjournal.com/content/5/1/6 DIABETOLOGY &
METABOLIC SYNDROME
REVIEW Open Access
Metformin: an old but still the best treatment for
type 2 diabetes
Lilian Beatriz Aguayo Rojas* and Marilia Brito Gomes*
Abstract
The management of T2DM requires aggressive treatment to achieve glycemic and cardiovascular risk factor goals.
In this setting, metformin, an old and widely accepted first line agent, stands out not only for its antihyperglycemic
properties but also for its effects beyond glycemic control such as improvements in endothelial dysfunction,
hemostasis and oxidative stress, insulin resistance, lipid profiles, and fat redistribution. These properties may have
contributed to the decrease of adverse cardiovascular outcomes otherwise not attributable to metformin’s mere
antihyperglycemic effects. Several other classes of oral antidiabetic agents have been recently launched, introducing
the need to evaluate the role of metformin as initial therapy and in combination with these newer drugs. There is
increasing evidence from in vivo and in vitro studies supporting its anti-proliferative role in cancer and possibly a
neuroprotective effect. Metformin’s negligible risk of hypoglycemia in monotherapy and few drug interactions of
clinical relevance give this drug a high safety profile. The tolerability of metformin may be improved by using an
appropiate dose titration, starting with low doses, so that side-effects can be minimized or by switching to an
extended release form. We reviewed the role of metformin in the treatment of patients with type 2 diabetes and
describe the additional benefits beyond its glycemic effect. We also discuss its potential role for a variety of insulin
resistant and pre-diabetic states, obesity, metabolic abnormalities associated with HIV disease, gestational diabetes,
cancer, and neuroprotection.
Keywords: Metformin, Diabetes mellitus, Insulin, Resistance
Introduction co-activator, transducer of regulated CREB protein 2
The discovery of metformin began with the synthesis of (TORC2), resulting in its inactivation which conse-
galegine-like compounds derived from Gallega officinalis, quently downregulates transcriptional events that pro-
a plant traditionally employed in Europe as a drug for dia- mote synthesis of gluconeogenic enzymes [2]. Inhibition
betes treatment for centuries [1]. In 1950, Stern et al. of mitochondrial respiration has also been proposed to
discovered the clinical usefulness of metformin while contribute to the reduction of gluconeogenesis since it
working in Paris. They observed that the dose–response reduces the energy supply required for this process [3].
of metformin was related to its glucose lowering capacity Metformin’s efficacy, security profile, benefic cardio-
and that metformin toxicity also displayed a wide security vascular and metabolic effects, and its capacity to be
margin [1]. associated with other antidiabetic agents makes this drug
Metformin acts primarily at the liver by reducing glu- the first glucose lowering agent of choice when treating
cose output and, secondarily, by augmenting glucose up- patients with type 2 diabetes mellitus (TDM2).
take in the peripheral tissues, chiefly muscle. These
effects are mediated by the activation of an upstream
kinase, liver kinase B1 (LKB-1), which in turn regulates Metformin and pre-diabetes
the downstream kinase adenosine monophosphatase In 2000, an estimated 171 million people in the world
had diabetes, and the numbers are projected to double
by 2030. Interventions to prevent type 2 diabetes, there-
fore, have an important role in future health policies.
* Correspondence: lilian_aguayo@yahoo.com; mariliabgomes@gmail.com
Department of Medicine, Diabetes Unit, State University of Rio de Janeiro, Av Developing countries are expected to shoulder the ma-
28 setembro 77, Rio de Janeiro CEP20555-030, Brazil jority of the burden of diabetes [4]. One of the main
© 2013 Rojas and Gomes; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 2 of 15 http://www.dmsjournal.com/content/5/1/6 contributing factors to this burden is the Western life- 0.029), and 28.2% with lifestyle modification plus style which promotes obesity and sedentarism [5]. metformin (p = 0.022), as compared with the control Impaired glucose tolerance (IGT) and impaired fasting group [9] (Table 1). glucose (IFG) statuses are associated with increased and In a Chinese study, subjects with IGT randomly varying risk of developing type 2 diabetes mellitus. IGT assigned to receive either low-dose metformin (750 mg/ has been associated with an increased risk of cardiovas- day) or acarbose (150 mg/day) in addition to lifestyle cular events and may determine an increased mortality intervention were compared to a control group that only risk. The association of IFG with cardiovascular events, received life style intervention. Treatment with metformin however, has not been well established [6]. or acarbose produced large, significant, and similar risk When lifestyle interventions fail or are not feasible, reductions for new onset of T2DM of 77% and 88%, re- pharmacological therapy may be an important resource spectively; these reductions were larger than that of life- to prevent type 2 diabetes. Several different drug classes style intervention alone [10]. have been studied for this purpose. The persistence of the long-term effects obtained In their systematic review, Gillies et al. found that life- through DPP interventions were evaluated at an add- style and pharmacological interventions reduced the rate itional follow-up after a median of 5.7 years. Individuals of progression to type 2 diabetes in people with IGT and were divided in 3 groups: lifestyle, metformin, and that these interventions seem to be as effective as pharma- placebo. Diabetes incidence rates were similar between cological treatment. Although compliance was high, treat- treatment groups: 5.9 per 100 person-years (5.1–6.8) for ment effect was not sustained after treatment was lifestyle, 4.9 (4.2–5.7) for metformin, and 5.6 (4.8–6.5) stopped. According to the results of their meta-analysis, for placebo. Diabetes incidence 10 years since DPP lifestyle interventions may be more important in those randomization was reduced by 34% and 18% in the life- with higher mean baseline body mass index BMI [5]. style and metformin group, respectively [11] (Table 1). The best evidence for a potential role for metformin in The prevalence of pre-diabetes as well as the progression the prevention of type 2 diabetes comes from The Dia- rate to diabetes may differ between different populations, betes Prevention Program (DPP) trial. Lifestyle interven- making the application of results from certain studies of dif- tion and metformin reduced diabetes incidence by 58% ferent ethnical groups inappropriate. IGT is highly prevalent and 31%, respectively, when compared with placebo [7]. in native Asian Indians. This population has several unique At the end of the DPP study, patients were observed for features such as a young age of diabetes onset and lower a one to two week wash out period. Diabetes incidence BMI along with high rates of insulin resistance and lower increased from 25.2 to 30.6% in the metformin group and thresholds for diabetic risk factors [12]. Chinese individuals from 33.4 to 36.7% in the placebo group. Even after in- have a lower prevalence of diabetes and are less insulin re- cluding the wash out period in the overall analysis, sistant than Indians, so the results of the Chinese study may metformin still significantly decreased diabetes incidence not be applicable to Asian Indian individuals [13]. (risk ratio 0.75, p = 0.005) compared with placebo [8]. In a meta-analysis of randomized controlled trials, These data suggest that, at least in the short-term, Salpeter et al. reported a reduction of 40% in the inci- metformin may help delay the onset of diabetes. The dence of new-onset diabetes with an absolute risk reduc- benefits of metformin were primarily observed in patients tion of 6% (95% CI, 4–8) during a mean trial duration of
Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 3 of 15
http://www.dmsjournal.com/content/5/1/6
and lower metformin dosage (250 mg twice or 3 times [23,24]. The glimepiride/metformin combination results
daily) in people of varied ethnicity [15]. in a lower HbA1c concentration and fewer hypoglycemic
events when compared to the glibenclamide/metformin
Metformin in the management of adult diabetic patients combination [25]. The use of metformin was associated
Current guidelines from the American Diabetes Associ- with reduced all-cause mortality and reduced cardiovas-
ation/European Association for the Study of Diabetes cular mortality. Metformin and sulfonylurea combin-
(ADA/EASD) and the American Association of Clinical ation therapy was also associated with reduced all-cause
Endocrinologists/American College of Endocrinology mortality [26].
(AACE/ACE) recommend early initiation of metformin Epidemiological investigations suggest that patients on
as a first-line drug for monotherapy and combination SUs have a higher cardiovascular disease event rate than
therapy for patients with T2DM. This recommendation those on metformin. Patients who started SUs first and
is based primarily on metformin’s glucose-lowering added metformin also had higher rates of cardiovascular
effects, relatively low cost, and generally low level of side disease events compared with those who started metformin
effects, including the absence of weight gain [16,17]. first and added SUs. These investigations are potentially
Metformin’s first-line position was strengthened by the affected by unmeasured confounding variables [27].
United Kingdom Prospective Diabetes Study (UKPDS)
observation that the metformin-treated group had risk Metformin and insulin
reductions of 32% (p = 0.002) for any diabetes-related Metformin as added to insulin-based regimens has been
endpoint, 42% for diabetes-related death (p = 0.017), and shown to improve glycemic control, limit changes in
36% for all-cause mortality (p = 0.011) compared with body weight, reduce hypoglycemia incidence, and to re-
the control group. The UKPDS demonstrated that duce insulin requirements (sparing effect), allowing a
metformin is as effective as sulfonylurea in controlling 15–25% reduction in total insulin dosage [28,29].
blood glucose levels of obese patients with type 2 dia- The addition of metformin to insulin therapy in type 1
betes mellitus [18]. Metformin has been also been shown diabetes is also associated with reductions in insulin-
to be effective in normal weight patients [19]. dose requirement and HbA1c levels [30,31].
Metformin in combination therapy Metformin and thiazolinediones
Although monotherapy with an oral hypoglycemic agent The addition of rosiglitazone to metformin in a 24-week
is often initially effective, glycemic control deteriorates randomized, double-blind, parallel-group study signifi-
in most patients which requires the addition of a second cantly decreased HbA1c concentration and improved insu-
agent. Currently, marketed oral therapies are associated lin sensitivity and HOMA ß cell function [32]. However, in
with high secondary failure rates [20]. Combinations of spite of preventing diabetes incidence, the natural course
metformin and insulin secretagogue can reduce HbA1c of declining insulin resistance may not be modified by a
between 1.5% to 2.2% in patients sub-optimally con- low dose of the metformin-rosiglitazone combination [33].
trolled by diet and exercise [21]. The ADOPT study (A Diabetes Outcome Progression
The optimal second-line drug when metformin mono- Trial) assessed the efficacy of rosiglitazone, as compared
therapy fails is not clear. All noninsulin antidiabetic to metformin or glibenclamide, in maintaining long-term
drugs when added to maximal metformin therapy are glycemic control in patients with recently diagnosed type
associated with similar HbA1c reduction but with 2 diabetes. Rosiglitazone was associated with more weight
varying degrees of weight gain and hypoglycemia risk. gain, edema, and greater durability of glycemic control;
A meta-analysis of 27 randomized trials showed that metformin was associated with a higher incidence of
thiazolidinediones, sulfonylureas, and glinides were gastrointestinal events and glibenclamide with a higher
associated with weight gain; glucagon-like peptide-1 risk of hypoglycaemia. [34].
analogs, glucosidase inhibitors, and dipeptidyl peptidase-4
inhibitors were associated with weight loss or no weight Metformin and glifozins
change. Sulfonylureas and glinides were associated with Dapagliflozin, a highly selective inhibitor of SGLT2, has
higher rates of hypoglycemia than with placebo. When demonstrated efficacy, alone or in combination with
combined with metformin, sulfonylureas and alpha- metformin, in reducing hyperglycemia in patients with
glucosidase inhibitors show a similar efficacy on HbA1c [22]. type 2 diabetes [35,36]. Studies are in development for
assessing the safety and efficacy of this combination.
Metformin and sulfonylureas
The combination of metformin and sulfonylurea (SU) is Metformin and α glicosidase inhibitor
one of the most commonly used and can attain a greater Acarbose reduces the bioavailability of metformin [37].
reduction in HbA1c (0.8–1.5%) than either drug alone However, it has been reported that the association ofRojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 4 of 15
http://www.dmsjournal.com/content/5/1/6
acarbose to metformin in sub-optimally controlled Results of the MiG TOFU reported that infants of dia-
patients reduced HbA1c by about 0.8-1.0% [38]. betic mothers exposed to metformin in utero and
examined at 2 years of age may present a reduction in
Metformin and incretin-based therapies insulin resistance, probably related to an increase in sub-
DDPIV prolongs the duration of active glucagon-like cutaneous fat [48].
peptide 1 (GLP-1) by inhibiting DPPIV peptidase, an en- Longer follow-up studies will be required to determine
zyme which cleaves the active form of the peptide. This metformin’s impact on the development of obesity and
action results in an improvement of insulin secretion as metabolic syndrome in offspring.
a physiological response to feeding. The mechanism of
DPPIV inhibitors is complementary to that of metformin Metformin use in childhood and adolescence
which improves insulin sensitivity and reduces hepatic Type 2 diabetes mellitus has dramatically increased in
glucose production, making this combination very useful children and adolescents worldwide to the extent that
for achieving adequate glycemic control [39]. Metformin has been labeled an epidemic [49]. Before 1990, it was a
has also been found to increase plasma GLP-1 levels, rare condition in the pediatric population; by 1999, the
probably by either direct inhibition of DPPIV or by incidence varied from 8% to 45%, depending on geo-
increased secretion, leading to reduced food intake and graphic location, and was disproportionally represented
weight loss [40]. among minority groups [50]. There are few studies of
Saxagliptin added to metformin led to clinically and metformin use in the pediatric population. Most of them
statistically significant reductions in HbA1c from base- are of short duration and heterogeneous designs.
line versus metformin/placebo in a 24-week randomized, The beneficial role of metformin in young patients with
double-blind, placebo-controlled trial. Saxagliptin at type 2 diabetes has been demonstrated in a randomized, con-
doses of 2.5, 5, and 10 mg plus metformin decreased A1 trolled trial which showed a significant decrease in fasting
by 0.59%, 0.69%, and 0.58%, respectively, in comparison blood glucose, HbA1c, weight, and total cholesterol. The
to an increase in the metformin plus placebo group most frequently reported adverse events were abdominal
(+0.13%); p < 0.0001 for all comparisons [41]. pain, diarrhea, nausea/vomiting, and headaches. There were
A meta-analysis of 21 studies examined incretin-based no cases of clinical hypoglycemia, lactic acidosis, or clinically
therapy as an add-on to metformin in patients with T2DM significant changes in physical examinations [51]. When
for 16–30 weeks; 7 studies used a short-acting GLP-1 re- compared to glimepiride (1–8 mg once daily), metformin
ceptor agonist (exenatide BID), 7 used longer acting GLP-1 (500–1000 mg twice daily) lowered HbA1c toRojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 5 of 15
http://www.dmsjournal.com/content/5/1/6
with a higher risk of developing diabetes and of progres- this study, the UKPDS, the largest randomized clinical
sion to fibrosis and cirrhosis [55] with an increased rela- trial in the newly-diagnosed type 2 diabetic population
tive risk of cardiovascular events or death [56]. The true largely free of prior major vascular events, randomly
prevalence of NAFLD in children is underestimated. The assigned treatment with metformin to a subgroup of
prevalence of steatosis in obese children was estimated overweight individuals (>120% of ideal body weight). In
to be 38% in a large retrospective autopsy study [57]. 1990, another subgroup of patients (n = 537), who were
Currently, the best supported therapy for NAFLD is receiving the maximum allowed dosage of sulfonylurea,
gradual weight loss through exercise and nutritional sup- were randomized either to continue sulfonylurea therapy
port [58]. Metformin is associated with short-term or to allow an early addition of metformin [18].
weight loss, improvement of insulin sensitivity, and Metformin provided greater protection against the de-
decreased visceral fat [59]. A reduction in ALT, GGT, velopment of macrovascular complications than would
and fatty liver incidence and severity has also been be expected from its effects upon glycemic control
described with metformin use [60]. alone. It had statistically significant reductions in the risk
Metformin has been used increasingly in obese chil- of all-cause mortality, diabetes-related mortality (p =
dren with hyperinsulinemia although there are no strong 0.017), and any end-point related to diabetes (p = 0.002),
evidence-based studies supporting its use for this clinical but not in myocardial infarction (p = 0.052) [18]. The
condition. A moderate improvement in body muscular UKPDS pos-trial reported significant and persistent risk
index (BMI) and insulin sensitivity has been reported reductions for any diabetes-related end point (21%, p =
with the use of metformin [61,62]. Heart rate recovery 0.01), myocardial infarction (33%, p = 0.005), and death
(HRR) may also improve due to improved parasympa- from any cause (27%, p = 0.002) [73].
thetic tone, paralleling improvements in BMI, insulin Following UKPDS, other studies have reported signifi-
levels, and insulin sensitivity [61]. HRR has been cant improvement of all-cause mortality and cardiovascu-
considered a predictor of mortality and cardiovascular lar mortality (Table 2). A retrospective analysis of patients
disease in otherwise healthy subjects [63]. A poor HRR databases in Saskatchewan, Canada reported significant
has also been linked to insulin resistance [64] and to a reductions for all-cause mortality and cardiovascular mor-
higher risk for developing T2DM [65]. tality of 40% and 36%, respectively [26]. The PRESTO trial
Metformin may not be as effective as behavioral showed significant reductions of any clinical event (28%),
interventions in reducing BMI and when compared with myocardial infarction (69%), and all-cause mortality (61%)
drugs that are licensed for obesity, its effects are moder- [74]. The HOME trial reported a decreased risk of
ate [66]. developing macrovascular disease [75]. In non-diabetic
subjects with normal coronary arteriography but also with
Effects of metformin on vascular protection two consecutive positive (ST depression > 1 mm) exercise
Effects on cardiovascular mortality tolerance test, an 8-week period on metformin improved
Diabetic patients are at high risk of cardiovascular maximal ST-segment depression, Duke score, and chest
events, particularly of coronary heart disease by about pain incidence compared with placebo [76]. A recent
3-fold [67,68]. It has been stated that type 2 diabetic meta-analysis suggested that the cardiovascular effects of
patients without a previous history of myocardial infarc- metformin could be smaller than had been hypothesized
tion have the same risk of coronary artery disease (CAD) on the basis of the UKPDS; however, its results must be
as non-diabetic subjects with a history of myocardial in- interpreted with caution given the low number of
farction [69]. This has led the National Cholesterol Edu- randomized controlled trials included [77].
cation Program to consider diabetes as a coronary heart
disease risk equivalent [70]. Although there is no doubt Metformin and heart failure
that there is an increased risk of CAD events in diabetic The risk of developing cardiac heart failure (CHF) in
patients, there is still some uncertainty as to whether the diabetic individuals nearly doubles as the population
cardiovascular risk conferred by diabetes is truly equiva- ages [77]. DM and hyperglycemia are strongly implicated
lent to that of a previous myocardial infarction [71]. as a cause for the progression from asymptomatic left
In 1980, Scambato et al. reported that, in a 3-year ob- ventricular dysfunction to symptomatic HF, increased
servational study of 310 patients with ischaemic cardio- hospitalizations for HF, and an overall increased mortal-
myopathy, patients treated with metformin had reduced ity risk in patients with chronic HF [78]. Despite all its
rates of re-infarction, occurrence of angina pectoris, benefits, metformin is contraindicated in patients with
acute coronary events other than acute myocardial in- heart failure due to the potential risk of developing lactic
farction, and death in patients [72]. The largest effect acidosis, a rare but potentially fatal metabolic condition
was seen in re-infarction rates; a post hoc analysis resulting from severe tissue hypoperfusion [79]. The US
showed that this effect was significant (p = 0.003). After Food and Drug Administration removed the heart failureRojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 6 of 15
http://www.dmsjournal.com/content/5/1/6
Table 2 Metformin effects on vasculoprotection
Study Design Duration Key findings
UKPDS 33 [18] Prospective 10 yr Significant reduction in all-cause mortality, diabetes related mortality, and any end-point related to
diabetes.
Sgambato et al. [72] Retrospective 3 yr Trend towards reduction in angina symptoms (p = 0.051). Significant lower re-infarction rates.
Johnson et al. [24] Retrospective 9 yr Reduction of all-cause mortality and of cardiovascular mortality
Kao et al. [74] Prospective 2 yr Significant risk reduction for any clinical event, myocardial infarction and all-cause mortality
Jadhav et al. [76] Prospective 8 weeks Improved maximal ST depression, Duke score, and chest pain incidence
Kooy et al. [75] Prospective 4, 3 yr Reduction of the risk of developing macrovascular disease
contraindication from the packaging of metformin al- pathway [86], coagulation [87], oxidative stress and
though a strong warning for the cautious use of glycation [88-92], endothelial dysfunction [88-90], haemo-
metformin in this population still exists [80]. stasis [88,91-93], insulin resistance improvement [94],
Several retrospective studies in patients with CHF and dia- lipid profiles [95,96], and fat redistribution [97,98]. Some
betes reported lower risk of death from any cause [81-83], of these mechanisms are described below.
lower hospital readmissions for CHF [81], and hospitalizations
for any cause [81,82]. A recent review concluded that CHF Beyond glycemic control
could not be considered an absolute contraindication for The UKPDS recruited patients with newly diagnosed
metformin use and also suggest its protective effect in redu- type 2 diabetes and demonstrated that tight glycemic
cing the incidence of CHF and mortality in T2DM [83]. This control has beneficial effects on microvascular end
protective effect may due to AMPK activation and decrease in points. However, it failed to show improvements in
cardiac fibrosis [83]. macrovascular outcomes. The improved cardiovascular
In a prospective 4-year study, 393 metformin-treated disease (CVD) risk in overweight diabetic patients
patients with elevated serum creatinine between 1.5– treated with metformin was attributed to its effects
2.5 mg/dL and coronary artery disease, CHF, or chronic extending beyond glycemic control [18].
obstructive pulmonary disease (COPD) were randomized
into two groups. One group continued metformin ther- Effects on the inflammatory pathway
apy while the other was instructed to discontinue The benefits of metformin on macrovascular complications
metformin. Patients with CHF had either New York of diabetes, separate from its conventional hypoglycemic
Heart Association (NYHA) Class III or Class IV CHF effects, may be partially explained by actions beyond
and were receiving diuretic and vasodilatation drugs. glycemic control, particularly by actions associated with in-
There were no differences between groups in all-cause flammatory and atherothrombotic processes [86]. Metformin
mortality, cardiovascular mortality, rate of myocardial can act as an inhibitor of pro-inflammatory responses
infarction, or rate of cardiovascular events [84]. through direct inhibition of NF-kB by blocking the PI3K–
Patients with DM and advanced, systolic HF (n = 401) Akt pathway. This effect may partially explain the apparent
were divided into 2 groups based on the presence or ab- clinical reduction of cardiovascular events not fully attribut-
sence of metformin therapy. The cohort had a mean age able to metformin’s anti-hyperglycemic action [86].
of 56 ± 11 years and left ventricular ejection fraction Some studies also point to a modest effect on inflam-
(LVEF) of 24 ± 7% with 42% and 45% being NYHA III matory markers in subjects with IGT in T2DM [87]
and NYHA IV, respectively. Twenty-five percent (n = 99) while others have found no effect at all [88].
were treated with metformin therapy. Metformin-treated
patients had a higher BMI, lower creatinine, and were Effects on oxidative stress
less often on insulin. One-year survival in metformin- Oxidative stress is believed to contribute to a wide range
treated and non-metformin-treated patients was 91% of clinical conditions such as inflammation, ischaemia-
and 76%, respectively (p = 0.007). After a multivariate reperfusion injury, diabetes, atherosclerosis, neurodegen-
adjustment for demographics, cardiac function, renal eration, and tumor formation [99].
function, and HF medications, metformin therapy was Metformin has antioxidant properties which are not
associated with a non-significant trend of improved sur- fully characterized. It reduces reactive oxygen species
vival [85]. (ROS) by inhibiting mitochondrial respiration [100] and
Many different mechanisms, beyond glycemic control, decreases advanced glycosylation end product (AGE) in-
have been implicated in vascular protection induced by directly through reduction of hyperglycemia and directly
metformin such as improvements in the inflammatory through an insulin-dependent mechanism [101].Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 7 of 15
http://www.dmsjournal.com/content/5/1/6
There is some evidence that metformin also has a The mechanisms by which metformin contributes to
beneficial effect on some components of the antioxidant weight loss may be explained through the reduction in
defense system. It can upregulate uncoupled proteins 2 gastrointestinal absorption of carbohydrates and insulin
(UCP2) in adipose tissue [102] and can also cause an in- resistance [95], reduction of leptin [95] and ghrelin levels
crease in reduced glutathione [100]. after glucose overload [96], and by induction of a
Metformin has been proposed to cause a mild and transi- lipolitic and anoretic effect by acting on glucagon–like
ent inhibition of mitochondrial complex I which decreases peptide 1 [40].
ATP levels and activates AMPK-dependent catabolic
pathways [100], increasing lipolysis and ß-oxidation in white Effects on lipid profile
adipose tissue [102] and reducing neoglucogenesis [2]. The Metformin is associated with improvements in lipopro-
resultant reduction in triglycerides and glucose levels could tein metabolism, including decreases in LDL-C [95],
decrease metylglyoxal (MG) production through lipoxidation fasting and postprandial TGs, and free fatty acids [106].
and glycoxidation, respectively [99,101].
Recently a study described a putative mechanism relat- Effects on blood pressure
ing metformin action and inhibition of oxidative stress, The hypertension associated with diabetes has an unclear
inflammatory, and proapoptotic markers [103]. In this pathogenesis that may involve insulin resistance. Insulin
study, treatment of bovine capillary endothelial cells resistance is related to hypertension in both diabetic and
incubated in hyperglycemic medium with metformin non-diabetic individuals and may contribute to hyperten-
was able to decrease the activity of NF-kB and others sion by increasing sympathetic activity, peripheral vascular
intracellular proteins related to cellular metabolic mem- resistance, renal sodium retention [107], and vascular
ory. The authors suggested that this action could be smooth muscle tone and proliferation [108,109].
mediated by histone deacetylase sirtuin 1 (SIRT-1), a Data of the effects of metformin on BP are variable,
multifunctional protein involved in many intracellular with neutral effects or small decreases in SBP and DBP
pathways related to metabolism, stress response, cell [110]. In the BIGPRO1 trial carried out in upper-body
cycle, and aging [103]. obese non-diabetic subjects with no cardiovascular
diseases or contraindications to metformin, blood pres-
Effects on endothelial function sure decreased significantly more in the IFG/IGT sub-
Type 2 diabetes is associated with a progressive and group treated with metformin compared to the placebo
generalized impairment of endothelial function that affects group (p < 0.03) [111].
the regulation of vasomotor tone, leucocyte adhesion,
hemostasis, and fibrinolysis. These effects are probably Effects on thyroid function
direct and not related to decreases in hyperglycemia [88]. Metformin decreases serum levels of thyrotropin (TSH)
Contradictory effects of metformin on endothelial to subnormal levels in hypothyroid patients that use
function have been described, however [89,90]. Mather levothyroxin (LT4) on a regular basis [112]. A significant
et al. reported that metformin has no effect on endothe- decrease in TSH (P < 0.001) without reciprocal changes
lium dependent blood flow but has a significant effect in any thyroid function parameter in diabetic patients
on endothelium independent blood flow and insulin re- had also been reported but only in hypothyroid subjects,
sistance reduction [89]. Conversely, Vitale et al. found not in euthyroid ones [113].
significant improvement of endothelium dependent flow The mechanism of the drop in TSH is unclear at this
without a significant effect on endothelium independent time. Some of the proposed explanations for this effect
response [90]. Further studies are necessary to establish are enhanced inhibitory modulation of thyroid hormones
the effect of metformin on endothelial function. on central TSH secretion, improved thyroid reserve in
patients with hypothyroidism [113], changes in the affin-
Effects on body weight ity or the number of thyroid hormone receptors,
Metformin may have a neutral effect on body weight of increased dopaminergic tone, or induced constituent ac-
patients with T2DM when compared to diet [18] or may tivation of the TSH receptor [112].
limit or decrease the weight gain experienced with
sulfonylureas [18], TDZ [104], insulin [29,75], HAART Metformin and HIV lypodystrofy
[97], and antipsychotics drugs [94]. Antiretroviral therapy has been associated with an
Modest weight loss with metformin has been observed increased prevalence of type 2 diabetes mellitus and in-
in subjects with IGT [15,18]. However, a meta-analysis sulin resistance among HIV-infected patients [114].
of overweight and obese non-diabetic subjects, found no Lipodystrophy, characterized by morphological (periph-
significant weight loss as either a primary or as second- eral lipoatrophy, localized fat accumulation) and meta-
ary outcome [105]. bolic changes (hyperlipidemia, insulin resistance andRojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 8 of 15
http://www.dmsjournal.com/content/5/1/6
hyperglycemia), is highly prevalent in patients on highly The human brain is characterized by an elevated oxida-
active antiretroviral therapy (HAART), occurring in 40% tive metabolism and low antioxidants enzymes, which
to 80% of patients [115]. increases the brain’s vulnerability to oxidative stress [125].
Nucleoside reverse transcriptase inhibitors (NRTIs), par- Oxidative stress has been implicated in a variety of neuro-
ticularly thymidine analogues (zidovudine and stavudine), logical diseases, including Alzheimer’s disease, Parkinson’s
have been associated with morphological changes, particu- disease, and amyotrophic lateral sclerosis disease [126].
larly extremity fat loss [116], while protease inhibitors Mitochondrial dysfunction has a pivotal role in oxidative
(PIs) have been associated with biochemical derangements stress. In this setting, the permeability transition pore
of glucose and lipids as well as with localized accumula- (PTP) acts as a regulator of the apoptotic cascade under
tion of fat [117]. stress conditions, triggering the release of apoptotic
Lifestyle modifications such as diet and exercise and proteins and subsequent cell death [127]. It was reported
switching antiretroviral therapies seems to be of limited that metformin prevents PTP opening and subsequent cell
value in reducing visceral abdominal fat (VAT). Metformin death in various endothelial cell types exposed to high glu-
has been shown to reduce VAT [97,98] but at the expense cose levels [128]. Metformin could interrupt the apoptotic
of accelerating peripheral fat loss [118]. Favorable effects on cascade in a model of ectoposide-induced cell death by
insulin levels [98], insulin sensitivity [119], weight [97], inhibiting PTP opening and blocking the release of
flow-mediated vasodilation [119], and lipid profiles [98,119] cytochrome-c. These events together with other factors
have also been described. from the mitochondrial intermembrane space are critical
processes in the apoptotic cascade [125].
Insulin has been shown to regulate a wide range of
Effects on hemostasis
processes in the central nervous system such as food in-
Therapeutic doses of metformin in type 2 diabetic
take, energy homeostasis, reproduction, sympathetic ac-
patients lower circulating levels of several coagulation
tivity, learning and memory [129], as well as neuronal
factors such as plasminogen activator inhibitor (PAI-1),
proliferation, apoptosis, and synaptic transmission [130].
von Williebrand Factor (vWF), tissue type plasminogen
With regard to ß amyloid, a report has shown that
activator [88], factor VII [91]. It has also direct effects
metformin increases ß amyloid in cells through an
on fibrin structure and function by decreasing factor
AMPK-dependent mechanism, independent of insulin sig-
XIII activity and changing fibrin structure [92].
naling and glucose metabolism. This effect is mediated by
Furthermore, plasma levels of PAI-1 and vWF, which
a transcriptional upregulation of ß secretase (BACE 1)
are secreted mainly by the impaired endothelium, have
which leads to an increase of ß amyloid [131]. However,
been shown to decrease with metformin therapy in non-
when insulin is added to metformin, it potentiates insulin’s
diabetic subjects [93].
effects on amyloid reduction, improves neuronal insulin
resistance, and impairs glucose uptake and AD-associated
Metformin and neuroprotection neuropathological characteristics by activating the insulin
Alzheimer’s disease (AD), one of the most common signaling pathway [129].
neurodegenerative diseases, has been termed type 3 dia- Metformin has been shown to promote rodent and
betes. It is a brain specific form of diabetes characterized human neurogenesis in culture by activating a protein kin-
by impaired insulin actions and neuronal insulin resist- ase C-CREB binding protein (PKC-CBP) pathway, recruiting
ance [120] that leads to excessive generation and accu- neural stem cells and enhancing neural function, particularly
mulation of amyloid oligomers, a key factor in the spatial memory function. It is noteworthy that neural stem
development of AD [121]. cells can be recruited in an attempt of endogeneously
The mechanisms of cerebral metabolism are still un- repairing the injured or regenerating brain [132]. In the con-
clear. A network of different factors is most likely re- text of metformin’s potential neuroprotective effect in vivo,
sponsible for its maintenance. The activated protein the capacity of the drug to cross the blood brain barrier
kinase (AMPK) forms a molecular hub for cellular meta- needs to be further elucidated. Provided that this crossing
bolic control [122]. Recent studies of neuronal models could occur, metformin may become a therapeutic agent
are pointing to possible AMPK roles beyond energy not only in peripheral and diabetes-associated vascular neur-
sensing with some reporting protective effects [123] opathy but also in neurodegenerative diseases.
while others report detrimental effects, particularly
under extreme energy depletion [124].
AMPK is activated in the brain by metabolic stresses Metformin and cancer
that inhibit ATP production such as ischemia, hypoxia, Patients with type 2 diabetes have increased risks of various
glucose deprivation, metabolic inhibitors (metformin), as types of cancer, particularly liver, pancreas, endometrium,
well as catabolic and ATP consuming processes [122]. colon, rectum, breast, and bladder cancer. Cancer mortalityRojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 9 of 15
http://www.dmsjournal.com/content/5/1/6
is also increased [133,134]. Many studies showed reduced in- response [136]. In an observational study of women with
cidence of different types of cancer in patients as well a type 2 diabetes, a decreased risk of breast cancer among
reduced cancer-related mortality in patients using metformin metformin users was only seen with long-term use [137].
(Table 3). Metformin use is associated with lower cancer-related
The underlying mechanisms of tumorigenesis in T2DM mortality. A prospective study (median follow-up time of
seem to be related to insulin resistance, hyperinsulinemia, 9.6 years) found that metformin use at baseline was
elevated levels of IGF-1 [140-142], and hyperglycemia with associated with lower cancer-related mortality and that this
the latter driving ATP production in cancer cells through association appeared to be dose dependent [138]. Diabetic
the glycolytic pathway, a mechanism known as the patients with colorectal cancer who were treated with
Warburg effect [142]. metformin had lower mortality than those not receiving
Metformin significantly reduces tumorigenesis and metformin [139]. Patients with type 2 diabetes exposed to
cancer cell growth although how it does it is not well sulfonylureas and exogenous insulin had a significantly
understood. It may be due to its effects on insulin reduc- increased risk of cancer-related mortality compared with
tion and hyperinsulinemia, and consequently on IGF-1 patients exposed to metformin. However, whether this
levels, which have mitogenic actions enhancing cellular increased risk is related to a deleterious effect of
proliferation,but may also involve specific AMPK- sulfonylurea and insulin or a protective effect of metformin
mediated pathways [133]. or due to some unmeasured effect related to both choice
Activation of AMPK leads to inhibition of mTOR of therapy and cancer risk is not known [147].
through phosphorylaton and subsequent activation of The proposed mechanisms of metformin anti-cancer
the tumor suppressor tuberous sclerosis complex 2 properties are not fully understood. Most are mainly
(TSC2). The mTOR is a key integrator of growth factor mediated through AMPK activation which requires LKB1,
and nutrient signals as well as a critical mediator of the a well-known tumor suppressor [2]. Some of these
PI3K/PKB/Akt pathway, one of the most frequently mechanisms may be through inhibition of cell growth
disregulated signaling pathways in human cancer [144]. [148], IGF-1 signaling [149], inhibition of the mTOR path-
Metformin may have additional anticancer properties in- way [150], reduction of human epidermal growth factor
dependent of AMPK, liver kinase 1 (LKB1), and TSC2. receptor type 2 (HER-2) expression (a major driver of
This may be related, in part, to the inhibition of Rag proliferation in breast cancer) [151], inhibition of angio-
GTPase-mediated activation of mTOR [145]. genesis and inflammation [152], induction of apoptosis
Patients with type 2 diabetes who are prescribed and protein 53 (p53) activation [153], cell cycle arrest
metformin had a lower risk of cancer compared to patients [137,154], and enhancement of cluster of differenciation 8
who did not take it. The reduced risk of cancer and cancer (CD8) T cell memory [155].
mortality observed in these studies has been consistently in
the range of 25% to 30% [135-139,145-147]. An observa-
tional cohort study with type 2 diabetics who were new Future roles for metformin in cancer therapy
metformin users found a significant decrease in cancer inci- In vitro and in vivo studies strongly suggest that
dence among metformin users (7.3%) compared to controls metformin may be a valuable adjuvant in cancer treat-
(11.6%). The unadjusted hazard ratio (95% CI) for cancer ment. Some of the proposed future roles yet to be
was 0.46 (0.40–0.53). The authors suggested a dose-related defined through further research are outlined as follows:
Table 3 Reduced incidence and cancer-related mortality in metformin treated patients
Author Study type Tumor type Region Total Follow Confounding adjustment *
participants up
(years)
Evans Pilot Not specified Tayside, 11,876 8 IMC, smoking, blood pressure, material deprivation
[135] Observational Scotland.
Study UK
Bodmer Retrospective Breast UK 22,661 10 Age, BMI, smoking, estrogen use, diabetes history, HbA1c, renal
[136] Case control failure, congestive heart failure, ischemic heart disease
Li [137] Prospective Pancreatic USA 1,836 4 Sex, age, smoking, DM-2, duration of diabetes, HbA1c, insulin
case–control use, oral antidiabetic medication, IMC, risk factors
Donadon Retrospective Hepatocellular Italy 1,573 12 Sex, age, BMI, alcohol abuse, HBV and HCV infection, DM-2, ALT
[138] Case–control carcinoma level
Libby Retrospective Colorectal Scotland. 8,000 9 Sex, age, BMI, HbA1c, deprivation
[139] cohort study UK
Other drug use
*Confounding adjustment: Adjustment of variables that could potentially interfere with cancer incidence.Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 10 of 15
http://www.dmsjournal.com/content/5/1/6
Tumor prevention order to prevent lactic acidosis. Some authors have
When compared to those on other treatments, suggested discontinuing its use when serum creatinine is
metformin users had a lower risk of cancer. A dose- above 1.5 mg/dL in men and 1.4 mg/dL in women [103]
relationship has been reported [138,144,145]. while others suggested a cut-off of 2.2 mg/dL and continu-
Adjunct in chemotherapy ous use even in the case of ischaemic cardiopathy, chronic
Type 2 diabetic patients receiving neo-adjuvant obstructive pulmonary disease, or cardiac failure [84].
chemotherapy for breast cancer as well as metformin As serum creatinine can underestimate renal dysfunc-
were more likely to have pathologic complete response tion, particularly in elderly patients and women, the use
(pCR) than patients not receiving it. However, despite the of estimated GFR (eGFR) has been advocated. The
increase in pCR, metformin did not significantly improve recommended eGFR thresholds are generally consistent
the estimated 3-year relapse-free survival rate [156]. with the National Institute for Health and Clinical Excel-
Tumor relapse prevention lence guidelines in the U.K. and those endorsed by the
Cancer stem cells may be resistant to Canadian Diabetes Association and the Australian Dia-
chemotherapeutic drugs, therefore regenerating the betes Society. Metformin may be continued or initiated
various tumor cell types and promoting disease relapse. with an eGFR of 60 mL/min per 1.73 m2 but renal func-
Low doses of metformin inhibited cellular tion should be monitored closely (every 3–6 months).
transformation and selectively killed cancer stem cells The dose of metformin should be reviewed and reduced
in four genetically different types of breast cancer in a (e.g. by 50% or to half-maximal dose) in those with an
mouse xenograft model. The association of metformin eGFR of 45 mL/min per 1.73 m2, and renal function
and doxorubicin killed both cancer stem cells and non- should be monitored closely (every 3 months). Metformin
stem cancer cells in culture. This may reduce tumor should not be initiated in patients at this eGFR [162]. The
mass and prevent relapse more effectively than either drug should be stopped once eGFR falls to 30 mL/min per
drug used as monotherapy [157]. 1.73 m2. Frid et al. supports these recommendations
through findings that above 30 ml/min/1.73 m2 metformin
Metformin contraindications levels rarely goes above 20 mmol/l, which seems to be a
Metformin is contraindicated in patients with diabetic safe level [163].
ketoacidosis or diabetic precoma, renal failure or renal Another clinical condition associated with lactic acid-
dysfunction, and acute conditions which have the poten- osis in patients using metformin is heart failure [79].
tial for altering renal function such as: dehydration, se-
vere infection, shock or intravascular administration of
iodinated contrast agents, acute or chronic disease Adverse effects
which may cause tissue hypoxia (cardiac or respiratory Gastrointestinal intolerance occurs quite frequently in
failure, recent myocardial infarction or shock), hepatic the form of abdominal pain, flatulence, and diarrhea
insufficiency, and acute alcohol intoxication in the case [164]. Most of these effects are transient and subside
of alcoholism and in lactating women [158]. Several once the dose is reduced or when administered with
reports in literature related an increased risk of lactic meals. However, as much as 5% of patients do not toler-
acidosis with biguanides, mostly phenformin, with an ate even the lowest dose [165].
event rate of 40–64 per 100,000 patients years [159] About 10–30% of patients who are prescribed metformin
whereas the reported incidence with metformin is 6.3 have evidence of reduced vitamin B12 absorption due to
per 100,000 patients years [160]. calcium-dependent ileal membrane antagonism, an effect
Structural and pharmacokinetic differences in metformin that can be reversed with supplemental calcium [166]. This
such as poor adherence to the mitochondrial membrane, vitamin B12 deficiency is rarely associated with megalo-
lack of interference with lactate turnover, unchanged excre- blastic anemia [167].
tion, and inhibition of electron transport and glucose oxida- A multicentric study reported a mean decrease of 19%
tion may account for such differences [161]. and 5% in vitamin B12 and folate concentration, respect-
Despite the use of metformin in cases where it is ively [168]. Vitamin B12 deficiency has been related with
contraindicated, the incidence of lactic acidosis has not dose and duration of metformin use and occurs more
increased. Most patients with case reports relating frequently among patients that use it for more than 3 -
metformin to lactic acidosis had at least one or more years and in higher doses [169].
predisposing conditions for lactic acidosis [161]. Other adverse reactions are sporadic, such as
Renal dysfunction is the most common risk factor leucocytoclastic vasculitis, allergic pneumonitis [170],
associated with lactic acidosis but so far there is no clear cholestatic jaundice [171], and hemolytic anaemia [172].
evidence indicating at which level of renal dysfunction Hypoglycemia is very uncommon with metformin
metformin should be discontinued or contraindicated in monotherapy [173] but has been reported in combinationRojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 11 of 15
http://www.dmsjournal.com/content/5/1/6
regimens [174], likely due to metformin potentiating other Conclusions
therapeutic agents. In recent years, metformin has become the first-line ther-
apy for patients with type 2 diabetes. Thus far, metformin is
Drug interactions the only antidiabetic agent which has shown reduced
Clinically significant drug interactions involving metformin macrovascular outcomes which is likely explained by its
are rare. Some cationic agents such as amiloride, digoxin, effects beyond glycemic control. It has also been employed
morphine, procainamide, quinidine, quinine, ranitidine, as an adjunct to lifestyle modifications in pre-diabetes and
triamterene, trimethoprim, and vancomycin that are insulin-resistant states. A large amount of evidence in lit-
eliminated by renal tubular secretion may compete with erature supports its use even in cases where it would be
metformin for elimination. Concomitant administration of contra-indicated mainly due to the fear of lactic acidosis
cimetidine, furosemide, or nifedipine may also increase the which has been over-emphasized as the available data sug-
concentration of metformin. Patients receiving metformin gest that lactate levels and risk of lactic acidosis do not
in association with these agents should be monitored for differ appreciably in patients taking this drug versus other
potential toxicity. Metformin should be discontinued at glucose-lowering agents. It has also recently gained atten-
least 48 hours prior to the administration of iodinated con- tion as a potential treatment for neurodegenerative diseases
trast media which can produce acute renal failure and such as Alzheimer’s disease.
should only be restarted if renal function is normal [175].
Abbreviations
ACE: Angiotensin converting enzyme; AD: Alzheimeir disease; AGE: Advanced
Tolerability
glycosilation end product; AMPK: Adenosine monophosfatase protein kinase;
Gastrointestinal side-effects are common with the use of BACE 1: Beta-amyloid cleaving enzyme- 1; BMI: Body muscular index;
metformin of standard release and are usually associated BP: Blood pressure; CAD: Coronary artery disease; CDK: Cyclin dependent
kinase; CHF: Cardiac heart failure; CPR: Complete pathologic response;
with rapid titration and high-dose initiation of metformin. CREB: cAMP responsive element binding protein; CsA: Cyclosporin A;
These effects are generally transient, arise early in the CVD: Cardiovascular disease; DDPPIV: Dipeptidyl peptidase IV; DM: Diabetes
course of treatment, and tend to subside over time mellitus; DYm: Mitochondrial membrane potential; FPG: Fasting plasma
glucose; GDM: Gestacional diabetes mellitus; GFR: Glomerular filtration rate;
[176]. The gastrointestinal side-effects can be addressed eGFR: Estimated glomerular filtration rate; GLP-1: Glucagon like peptide 1;
by taking the agent with meals, reducing the rate of dose HAART: Highly active antiretroviral therapy; HALS: HIV associated
escalation, or transferring to a prolonged-release formu- lipodystrophy syndrome; HIV: Human imunodeficiency virus; HER-2: Human
epidermal growth factor receptor type 2; HF: Heart failure; HOMA-
lation [177]. IR: Homeostatic model assessment – insulin resistance; IFG: Impaired fasting
Some studies point to a dose-related relationship of glucose; IGT: Impaired glucose tolerance; LKB-1: Liver kinase 1; LSM: Lifestyle
the incidence of side-effects [178] whereas other evi- modification; MET: Metformin; MG: Metylglyoxal; mTOR: Mammalian target of
rapamycin; NF-KB: Nuclear factor kappa beta; NRTIs: Nucleoside reverse
dence gives no support for a dose-related effect of transcriptase inhibitors; OGTT: Oral glucose tolerance test; PAI-1: Plasminogen
metformin on the gastrointestinal system [179]. activator inhibitor; PCOS: Policystic ovary syndrome; PIs: Protease inhibitors;
PTP: Permeability transition pore; ROS: Reactive oxigen species; SIRT-1: Sirtuin
1; T2DM: Type 2 diabetes mellitus; TCS2: Tuberous sclerosis complex 2;
Metformin XR
TORC2: Transducer of regulated CREB protein 2; TZP: Triazepinone;
The metformin XR formulation releases the active drug UCPs: Uncoupled proteins; VEGF: Vascular endothelial growth factor;
through hydrated polymers which expand after uptake Vwf: Von Williebrand fator.
of fluid, prolonging gastric residence time which leads to
slower drug absorption in the upper gastrointestinal Competing interests
The authors declare that they have no competing interests.
tract and allows once-daily administration [180].
A prospective open label study assessed metformin XR ef-
Authors’ contributions
fectiveness on three cardiovascular risk factors: blood glucose Lilian Beatiz Aguayo Rojas drafted the manuscript and Marilia Brito Gomes
(HbA1c, fasting blood glucose, and postprandial blood glu- reviewed and edited the manuscript. Both authors read and approved the
cose); total cholesterol, LDL cholesterol, HDL cholesterol; final manuscript.
and triglycerides and blood pressure. No significant
Authors’ information
differences were observed by any anthropometric, clinical, or Lilian Beatriz Aguayo Rojas is post graduate student at the State University of
laboratory measures except for plasma triglycerides which Rio de Janeiro, Diabetes Unit, Internal Medicine Department.
were lower in the group switched to metformin XR [181]. Marilia Brito Gomes is an Associate Professor at the State University of Rio de
Janeiro, Diabetes Unit, Internal Medicine Department.
Metformin tolerability as well as patient acceptance was
greater in the group switched to metformin XR. Other stud- Received: 12 December 2012 Accepted: 5 February 2013
ies have found good to excellent glycemic control with Published: 15 February 2013
metformin XR in type 2 diabetic patients who did not have
well-controlled diet and exercise alone [182]. Metformin XR References
1. Godarzi MO, Brier-Ash M: Metformin revisited: re-evaluation of its
has been associated with improved tolerability [182] and properties and role in the pharmacopoeia of modern antidiabetic
increased compliance [183]. agents. Diabetes Obes Metab 2005, 5:654–665.Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6 Page 12 of 15
http://www.dmsjournal.com/content/5/1/6
2. Shaw RJ, Lamia KA, Vasquez D, et al: The kinase LKB1 mediates glucose 24. Hanefeld M, Brunetti P, Schhernthaner GH, et al: One year glycemic control
homeostasis in liver and therapeutic effects of metformin. Science 2005, with sulphonylurea plus pioglitazone versus sulphonylurea plus
310:1642–1646. metformin in patients with type 2 diabetes. Diabetes Care 2004,
3. El-Mir MY, Nogueira V, Fontaine E, et al: Dimethylbiguanide inhibits cell 27:141–147.
respiration via an indirect effect targeted on the respiratory chain 25. González-Ortiza M, Guerrero-Romero J, Violante-Ortiz R, et al: Efficacy of
complex I. J Biol Chem 2000, 275:223–228. glimepiride/metformin combination versus glibenclamide/metformin in
4. Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes. patients with uncontrolled type 2 diabetes mellitus. J Diabetes
Estimates for the year 2000 and projections for 2030. Diabetes Care 2004, Complications 2009, 23:376–379.
27:1047–1053. 26. Johnson JA, Majumdar SR, Simpson SH, et al: Decreased mortality
5. Guillies C, Abram KR, Lambert PC, Cooper NJ, Sutton AJ, et al: associated with the use of metformin compared with sulfonylurea
Pharmacological and lifestyle interventions to prevent or delay type 2 Monotherapy in type 2 diabetes. Diabetes Care 2002, 25:2244–2248.
diabetes in people with impaired glucose tolerance: systematic review 27. Evans JM, Ogston SA, Emslie-Smith A, Morris AD: Risk of mortality and
and meta-analysis. BMJ 2007, 334:299. adverse cardiovascular outcomes in type 2 diabetes: a comparison of
6. Petersen J, Mc Guire D: Impaired glucose tolerance and impaired fasting patients treated with sulfonylureas and metformin. Diabetologia 2006,
glucose – a review of diagnosis, clinical implications and management. 49:930–936.
Diabetes Vasc Dis Res 2005, 2(1):9–15. 28. Giugliano D, Quatraro A, Consoli G, et al: Metformin for obese, insulin-
7. Diabetes Prevention Program Research Group: Reduction in the incidence treated diabetic patients: improvement in glycaemic control and
of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med reduction of metabolic risk factors. Eur J Clin Pharmacol 1993, 44:107–112.
2002, 346:393–403. 29. Lund SS, Tarnow L, Frandsen M, et al: Combining insulin with metformin
8. Diabetes Prevention Program Research Group: Effects of withdrawal from or an insulin secretagogue in non-obese patients with type 2 diabetes:
metformin on the development of diabetes in the diabetes prevention 12 month, randomised, double blind trial. BJ 2009, 339:b4324.
program. Diabetes Care 2003, 26(4):977–980. 30. Vella S, Buetow L, Royle P, et al: The use of metformin in type 1 diabetes:
9. Ramachandran A, Snehalatha C, Mukesh M, et al: Indian diabetes a systematic review of efficacy. Diabetologia 2010, 53(5):809–820.
prevention programme (IDPP). the Indian diabetes prevention 31. Abdelghaffar S, Attia AM: Metformin added to insulin therapy for type 1
programme shows that lifestyle modification and metformin prevent diabetes mellitus in adolescents. Cochrane Database Syst Rev 2009,
type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (Issue 1):CD006691.
(IDPP-1). Diabetologia 2006, 49:289–297. 32. Bailey CJ, Bagdonas A, Rubes J, et al: Rosiglitazone-metformin fixed-dose
10. Yang W, Lin L, Qi J, et al: The preventive effect of acarbose and combination compared with uptritrated metformin alone in type
metformin on the IGT population from becoming diabetes mellitus: a 3- diabetes mellitus:a 24 week, multicenter, randomized, double-blind,
year multicentral prospective study. Chin J Endocrinol Metab 2001, parallel-group study. Clin Ther 2005, 27:1548–1561.
17:131–134. 33. Retnakaran R, Qi Y, Harris SB, Hanley AJ, Zinman B: Changes over time in
11. Diabetes Prevention Program Research Group: 10-year follow-up of glycemic control, insulin sensitivity, and beta-cell function in response to
diabetes incidence and weight loss in the Diabetes Prevention Program low-dose metformin and thiazolidinedione combination therapy in
Outcomes Study. Lancet 2009, 374(9702):1677–1686. patients with impaired glucose tolerance. Diabetes Care 2011,
12. Ramachandran A, Snehalatha C, Vijay V: Low risk threshold for acquired 34(7):1601–1604.
diabetogenic factors in Asian Indians. Diab Res Clin Pract 2004, 34. Scheen AJ: ADOPT study: which first-line glucose-lowering oral
65:189–195. medication in type 2 diabetes? Rev Med Liege 2007, 62(1):48–52.
13. Pan XR, Li GW, Hu YH, et al: Effects of diet and exercise in preventing 35. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M:
NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic
Diabetes Study. Diabetes Care 1997, 20:537–544. control over 2 weeks in patients with type 2 diabetes mellitus. Clin
14. Salpeter SR, Buckley NS, Kahn JA, et al: Meta-analysis: metformin treatment Pharmacol Ther 2009, 85:513–519.
in persons at risk for diabetes mellitus. Am J Med 2008, 121:149–157. 36. List JF, Woo V, Morales E, Tang W, Fiedorek FT: Sodium-glucose
15. Lily M, Godwin M: Treating prediabetes with metformin systematic cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care
review and meta-analysis. Can Fam Physician 2009, 55:363–369. 2009, 32:650–657.
16. American Diabetes Association: Summary of revisions to the 2011 clinical 37. Scheen AJ, de Magalhanes AC, Salvatore T, et al: Reduction of the acute
practice recommendations. Diabetes Care 2011, 34(Suppl 1):S3. bioavailability of metformin by the α glycosidase inhibitor acarbose in
17. Rodbard HW, Jellinger PS, Davidson JA, et al: Statement by an American normal man. Eur J Clin Invest 1994, 24(Suppl3):50–54.
association of clinical endocrinologists/American college of 38. Rosenstok J, Brown A, Fischer J, et al: Efficacy and safety of acarbose in
endocrinology consensus panel on type 2 diabetes mellitus. An metformin-treated patients with type 2 diabetes. Diabetes Care 1998,
algorithm for glycemic control. Endocr Pract 2009, 15(6):540–559. 21:2050–2055.
18. Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood 39. Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL: Dipeptidyl peptidase-4
glucose control with metformin on complications in overweight patients (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev
with type 2 diabetes (UKPDS 34). Lancet 1998, 352(9131):854–865. 2008, (2):CD006739.
19. Ito H, Ishida H, Takeuchi Y, et al: Long-term effect of metformin on blood 40. Mannucci E, Ognibene A, Cremasco F, et al: Effect of metformin on
glucose control in non-obese patients with type 2 diabetes mellitus. glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic
Nutr Metab 2010, 7:83. subjects. Diabetes Care 2001, 24:489–494.
20. Turner RC, Cull CA, Frighi V, Holman RR: Glycemic control with diet, 41. DeFronzo RA, Hissa MN, Garber AJ, for Saxagliptin Study Group, et al: The
sulfonylurea, metformin, or insulin in patients with type 2 diabetes: efficacy and safety of saxagliptin when added to metformin therapy in
progressive requirement for multiple therapies (UKPDS 49). JAMA 1999, patients with inadequately controlled type 2 diabetes with metformin
281:2005–2012. alone. Diabetes Care 2009, 32(9):1649–1655.
21. Gerich J, Raskin P, Jean-Louis L, et al: PRESERVE-beta: two-year efficacy 42. Deacon CF, Mannucci E, Ahrén B: Glycaemic efficacy of glucagon-like
and safety of initial combination therapy with nateglinide or glyburide peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as
plus metformin. Diabetes Care 2005, 28:2093–2099. add-on therapy to metformin in subjects with type 2 diabetes-a review
22. Phung OJ, Scholle JM, Talwar M, Coleman CI: Effect of noninsulin and meta analysis. Diabetes Obes Metab 2012, 14(8):762–767.
Antidiabetic drugs added to metformin therapy on glycemic control, 43. Charles B, Norris R, Xiao X, Hague W: Population pharmacokinetics of
weight gain, and hypoglycemia in type 2 diabetes. JAMA 2010, metformin in late pregnancy. Ther Drug Monit 2006, 28:67–72.
303(14):1410–1418. 44. Gutzin SJ, Kozer E, Magee LA, Feig DS, Koren G: The safety of oral
23. Charbonnel B, Shernthaner G, Brunetti P, et al: Long-term efficacy and hypoglycemic agents in the first trimester of pregnancy. a meta-analysis.
tolerability of add-on piogçitazone therapy to faliling monotherapy Can J Clin Pharmacol 2003, 10:179–183.
compared with addition of glicazide or metformin in patients with type 45. Gilbert C, Valois M, Koren G: Pregnancy outcome after first-trimester
2 diabetes. Diabetologia 2005, 48:1093–1104. exposure to metformin: a meta-analysis. Fertil Steril 2006, 86:658–663.You can also read
